The serine proteases are a class of enzymes, which includes elastase, chymotrypsin, cathepsin G, trypsin and thrombin. These proteases have in common a catalytic triad consisting of Serine-195, Histidine-57 and Aspartic acid-102(chymotrypsin numbering system). Human neutrophil elastase (HNE) is a proteolytic enzyme secreted by polymorphonuclear leukocytes (PMNs) in response to a variety of inflammatory stimuli. This release of HNE and its extracellular proteolytic activity are highly regulated and are normal, beneficial functions of PMNs. The degradative capacity of HNE, under normal circumstances, is modulated by relatively high plasma concentrations of xcex11-proteinase inhibitor (xcex1-PI). However, stimulated PMNs produce a burst of active oxygen metabolites, some of which (hypochlorous acid for example) are capable of oxidizing a critical methionine residue in xcex1-PI. Oxidized xcex1-PI has been shown to have limited potency as an HNE inhibitor and it has been proposed that alteration of this protease/antiprotease balance permits HNE to perform its degradative functions in localized and controlled environments.
Despite this balance of protease/antiprotease activity, there are several human disease states in which a breakdown of this control mechanism is implicated in the pathogenesis of the condition. Improper modulation of HNE activity has been suggested as a contributing factor in adult respiratory distress syndrome, septic shock and multiple organ failure. A series of studies also have indicated the involvement of PMNs and neutrophil elastase in myocardial ischemia-reperfusion injury. Humans with below-normal levels of xcex11-PI have an increased probability of developing emphysema. HNE-mediated processes are implicated in other conditions such as arthritis, periodontal disease, glomerulonephritis, dermatitis, psoriasis, cystic fibrosis, chronic bronchitis, atherosclerosis, Alzheimer""s disease, organ transplantation, corneal ulcers, and invasion behavior of malignant tumors.
There is a need for effective inhibitors of HNE as therapeutic and as prophylactic agents for the treatment and/or prevention of elastase-mediated problems.
In one embodiment, the present invention provides compounds of formula I 
wherein X and Y are independently O or N;
R1 is alkyl, xcex1, xcex1-dialkylalkylaryl or xcex1, xcex1-dialkylalkyl fused aryl-cycloalkyl wherein the cycloalkyl group is optionally substituted with two or more O atoms;
R2 and R3 are independently H or alkyl; or together form a ring consisting of 3-5 carbons in which one or more carbon atoms of the ring can optionally be replaced with heteroatoms selected from O, S or N wherein N is optionally substituted with H or alkyl, preferably one of R2 and R3 is H and the other is iso-propyl; and
R4 is alkyloxycarbonyl.
Preferably, compounds of the present invention comprise a 1,3,4 oxadiazole ring (i.e., X is N; Y is O).
In one preferred embodiment of the invention, R1 is alkyl, such as tert-butyl. In another embodiment, R1 is xcex1,xcex1-dialkylalkylaryl, such as an xcex1, xcex1-dimethylbenzyl group. In still another preferred embodiment, R1 is xcex1, xcex1-dialkylalkyl fused aryl-cycloalkyl wherein the cycloalkyl group is substituted with two O atoms, such as an xcex1,xcex1-dimethyl-(3,4-methylenedioxy)benzyl group. In yet another preferred embodiment, R2 and R3 are independent alkyl, such as isopropyl, or H. Preferably, R2 is isopropyl and R3 is H.
In another embodiment, the present invention provides compounds of formula II: 
wherein X and Y are independently O or N;
R1, R2, and R3 are as above;
Rxe2x80x22 and Rxe2x80x23 are independently H or alkyl; or together form a ring consisting of 3-5 carbon atoms in which one or more carbon atoms of the ring can optionally be replaced by heteroatoms selected from O, S or N,
wherein N is optionally substituted with H or alkyl;
A is a direct bond, xe2x80x94NHxe2x80x94 or xe2x80x94OC(O)xe2x80x94NHxe2x80x94;
R4 is H or halo; and
R5 is H, alkyl or arylalkyl; or
a pharmaceutically acceptable salt thereof.
Preferably, compounds of this embodiment of the present invention comprise a 1,3,4 oxadiazole ring (i.e., X is N; Y is O).
In one preferred embodiment of the invention, R1 is alkyl, such as tert-butyl. In another embodiment, R1 is xcex1,xcex1-dialkylalkyl fused aryl-cycloalkyl wherein the cycloalkyl group is substituted with two O atoms, such as an xcex1,xcex1-dimethyl-(3,4-methylenedioxy)benzyl group. In yet another embodiment, R1 is xcex1,xcex1-dialkylalkylaryl, such as an xcex1,xcex1-dimethylbenzyl group. In still another preferred embodiment, R2 and R3 are independently alkyl, such as isopropyl, or H. In a more preferred embodiment, R2 is isopropyl, R3 is H, and R2xe2x80x2 and R3xe2x80x2 are both H. Where R4 is halo, R4 may be Cl, F, I or Br, although preferably it is F.
As used herein, the term xe2x80x9coptionally substitutedxe2x80x9d means, when substituted, mono to fully substituted.
As used herein, the term xe2x80x9cindependentlyxe2x80x9d means that the substituents may be the same or different.
As used herein, the term xe2x80x9calkylxe2x80x9d means C1-C15, and preferably C1-C8. It will be understood that the alkyl group may be linear or branched.
As used herein, the term xe2x80x9cxcex1,xcex1-dialkylalkylarylxe2x80x9d means that the alkyl groups are substituted at the xcex1-positions to the oxadiazole ring or to the aryl group or both. One such example is an xcex1,xcex1-dialkylbenzyl, wherein the xcex1-substituents are preferably methyl, ethyl or propyl. A specific example is xcex1,xcex1-dimethylbenzyl. The term xe2x80x9cxcex1,xcex1-dialkylalkyl fused arylcycloalkylxe2x80x9d is defined to mean that the alkyl groups are substituted at the xcex1-positions to the oxadiazole ring or to the aryl group, and a cycloalkyl is fused to the aryl ring. One such example of an xe2x80x9cxcex1,xcex1-dialkylalkyl fused aryl-cycloalkylxe2x80x9d is an xcex1,xcex1-dialkyl-3,4-methylenedioxybenzyl group, wherein the xcex1-substituents are preferably methyl, ethyl or propyl; preferably they are methyl. A specific example includes the xcex1,xcex1-dimethyl-3,4-methylenedioxybenzyl group.
As used herein, the term alkyloxycarbonyl means alkyl-Oxe2x80x94C(O)xe2x80x94 wherein the meaning of alkyl is defined above. One such example of an alkyloxycarbonyl is methyloxycarbonyl and is defined by the formula CH3xe2x80x94Oxe2x80x94C(O)xe2x80x94.